The long-term objective of this work is a comprehensive analysis of the cardioprotective effects of volatile anesthetics. These agents are capable of reducing reversible and irreversible myocardial injury following coronary artery occlusion and reperfusion. Recently, it was found that a prior, brief exposure to the volatile anesthetic, isoflurane, can reduce myocardial infarct size after its discontinuation. This phenomenon has a strong similarity to ischemic preconditioning (IPC) in which a brief period of coronary artery occlusion and reperfusion renders myocardium resistant to infarction after a subsequent prolonged ischemic insult. Anesthetic preconditioning (APC) demonstrates a powerful cardioprotective effect with early and late memory phases. The major hypothesis to be tested in the present investigation is that volatile anesthetics directly produce late (24 hr after anesthetic exposure) APC against myocardial infarction and apoptosis and preserve mitochondrial function. The intracellular signal transduction pathways for late APC will be characterized in an in vivo rabbit model of myocardial infarction (measured by triphenyltetrazolium histochemical staining) and using bioassays of endogenous mediators. Specific Aims include: Aim I: To characterize the efficacy of late APC to reduce infarct size and apoptosis and preserve mitochondrial bioenergetics and to determine its relationship to ROS. Aim II: To identify the role of the sarc and/or mito KATP channel in late APC. Aim III: To characterize the role of NOS and COX in late APC. The proposed research represents an investigation into a clinically relevant problem because of the large number of patients wtih coronary artery disease undergoing anesthesia and the morbidity and mortality associated with perioperative myocardial ischemia and infarction. Volatile anesthetics have recently been shown to produce APC in patients undergoing coronary artery bypass graft surgery. Late APC may last longer and occur when ischemic events are most frequent (postoperatively). This proposal will systematically delineate mechanisms and subcellular loci responsible for the novel and unique cardioprotective effects of volatile anesthetics against ischemia and reperfusion injury.